Identification of type 2 diabetes loci in 433,540 East Asian individuals.

Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D)1,2; however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418 individuals with T2D and 356,122 healthy control individuals. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci that are newly implicated in predisposition to T2D. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. Previously undescribed associations include signals in or near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect the differentiation of muscle and adipose cells3. At another locus, expression quantitative trait loci at two overlapping T2D signals affect two genes-NKX6-3 and ANK1-in different tissues4-6. Association studies in diverse populations identify additional loci and elucidate disease-associated genes, biology, and pathways.

Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.

Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10-3) and candidate genes from knockout mice (P = 5.2 × 10-3). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.

Association of Cardiovascular Health Through Young Adulthood With Genome-Wide DNA Methylation Patterns in Midlife: The CARDIA Study.

BACKGROUND: Cardiovascular health (CVH) from young adulthood is strongly associated with an individual's future risk of cardiovascular disease (CVD) and total mortality. Defining epigenomic biomarkers of lifelong CVH exposure and understanding their roles in CVD development may help develop preventive and therapeutic strategies for CVD. METHODS: In 1085 CARDIA study (Coronary Artery Risk Development in Young Adults) participants, we defined a clinical cumulative CVH score that combines body mass index, blood pressure, total cholesterol, and fasting glucose measured longitudinally from young adulthood through middle age over 20 years (mean age, 25-45). Blood DNA methylation at >840 000 methylation markers was measured twice over 5 years (mean age, 40 and 45). Epigenome-wide association analyses on the cumulative CVH score were performed in CARDIA and compared in the FHS (Framingham Heart Study). We used penalized regression to build a methylation-based risk score to evaluate the risk of incident coronary artery calcification and clinical CVD events. RESULTS: We identified 45 methylation markers associated with cumulative CVH at false discovery rate <0.01 (P=4.7E-7-5.8E-17) in CARDIA and replicated in FHS. These associations were more pronounced with methylation measured at an older age. CPT1A, ABCG1, and SREBF1 appeared as the most prominent genes. The 45 methylation markers were mostly located in transcriptionally active chromatin and involved lipid metabolism, insulin secretion, and cytokine production pathways. Three methylation markers located in genes SARS1, SOCS3, and LINC-PINT statistically mediated 20.4% of the total effect between CVH and risk of incident coronary artery calcification. The methylation risk score added information and significantly (P=0.004) improved the discrimination capacity of coronary artery calcification status versus CVH score alone and showed association with risk of incident coronary artery calcification 5 to 10 years later independent of cumulative CVH score (odds ratio, 1.87; P=9.66E-09). The methylation risk score was also associated with incident clinical CVD in FHS (hazard ratio, 1.28; P=1.22E-05). CONCLUSIONS: Cumulative CVH from young adulthood contributes to midlife epigenetic programming over time. Our findings demonstrate the role of epigenetic markers in response to CVH changes and highlight the potential of epigenomic markers for precision CVD prevention, and earlier detection of subclinical CVD, as well.

Missense Genetic Variation of ICAM1 and Incident Heart Failure.

BACKGROUND: Intercellular adhesion molecule-1 (ICAM-1) is a cell surface protein that participates in endothelial activation and is hypothesized to play a central role in heart failure (HF). We evaluated associations of ICAM1 missense genetic variants with circulating ICAM-1 levels and with incident HF. METHODS AND RESULTS: We identified 3 missense variants within ICAM1 (rs5491, rs5498 and rs1799969) and evaluated their associations with ICAM-1 levels in the Coronary Artery Risk Development in Young Adults Study and the Multi-Ethnic Study of Atherosclerosis (MESA). We determined the association among these 3 variants and incident HF in MESA. We separately evaluated significant associations in the Atherosclerosis Risk in Communities (ARIC) study. Of the 3 missense variants, rs5491 was common in Black participants (minor allele frequency [MAF] > 20%) and rare in other race/ethnic groups (MAF < 5%). In Black participants, the presence of rs5491 was associated with higher levels of circulating ICAM-1 at 2 timepoints separated by 8 years. Among Black participants in MESA (n = 1600), the presence of rs5491 was associated with an increased risk of incident HF with preserved ejection fraction (HFpEF; HR = 2.30; [95% CI 1.25-4.21; P = 0.007]). The other ICAM1 missense variants (rs5498 and rs1799969) were associated with ICAM-1 levels, but there were no associations with HF. In ARIC, rs5491 was significantly associated with incident HF (HR = 1.24 [95% CI 1.02 - 1.51]; P = 0.03), with a similar direction of effect for HFpEF that was not statistically significant. CONCLUSIONS: A common ICAM1 missense variant among Black individuals may be associated with increased risk of HF, which may be HFpEF-specific.

Epigenetic Age Acceleration Reflects Long-Term Cardiovascular Health.

[Figure: see text].

Progressive reduction in circulating levels of carotenoids and other micronutrients in patients with chronic pancreatitis.

BACKGROUND: Although micronutrients modulate immunity and inflammation, it remains elusive whether they are implicated in the development and progression of chronic pancreatitis (CP). This study aimed to investigate differences in the circulating levels of selected carotenoids and vitamins between CP and controls and trends in the levels of these micronutrients across controls, early CP, and definite CP. METHODS: Demographic and lifestyle data were extracted from medical records for 53 patients with CP (13 early and 38 definite) and obtained using a questionnaire for 52 controls. Plasma ß-carotene, lycopene, cryptoxanthin, zeaxanthin, and α-tocopherol and serum 25(OH)D, folate, IL-6, TNF-α, and MCP-1 were measured with state-of-the-art methods. RESULTS: The levels of all micronutrients (except folate) were significantly lower in CP than in controls. There was a progressive decrease in the levels of these micronutrients across controls, early CP, and definite CP (all p values for trend: ≤0.0012); e.g., plasma lycopene was 36.6, 21.5, and 14.5 µg/dL for controls, early CP, and definite CP, respectively. After adjustment for confounders, there were strong, inverse associations between the levels of all micronutrients (except folate) and CP (e.g., OR (95% CI) for ≥ median vs.

Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.

Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.

The Association of Serum Carotenoids, Tocopherols, and Ascorbic Acid With Rapid Kidney Function Decline: The Coronary Artery Risk Development in Young Adults (CARDIA) Study.

OBJECTIVE: Nutritional intervention targeting dietary intake modification is a major component of treatment for chronic kidney disease; however, little is known about the relationship between dietary intake and kidney function decline in individuals with preserved kidney function. DESIGN AND METHODS: In this prospective cohort study we examined the association of biomarkers of dietary intake with kidney function decline over a 5-year interval in 2,152 men and women with cystatin-C-based estimated glomerular filtration rate > 60 mL/minute/1.73 m2 from the Coronary Artery Risk Development in Young Adults study. The biomarkers of interest included carotenoids, tocopherols, and ascorbic acid. Multivariable logistic regression was used to explore the relationship between serum concentrations of the sum of 4 carotenoids (α-carotene, ß-carotene, ß-cryptoxanthin, and lutein/zeaxanthin), lycopene, α-tocopherol, γ-tocopherol, and ascorbic acid and rapid kidney function decline, defined as .15% decline in cystatin-C-based estimated glomerular filtration rate over 5 years. RESULTS: During the 5-year follow-up, 290 participants (13.5%) experienced rapid kidney function decline. Relative to individuals in the lowest quartile of serum carotenoids, those in the highest quartile had significantly lower odds of rapid kidney function decline in the fully adjusted model (odds ratio, 0.51; 95% confidence interval [CI], 0.32-0.80; P trend, .02). No association of levels of serum tocopherols, ascorbic acid, or lycopene with kidney function decline was found. There was no evidence that results differed for individuals with hypertension or diabetes. CONCLUSIONS: These results demonstrate that higher serum carotenoid levels, reflective of a fruit- and vegetable-rich dietary pattern, inversely associate with rapid kidney function decline in early middle adulthood and provide insight into how diet might play a role in chronic kidney disease prevention.

Associations of Circulating 25-Hydroxyvitamin D3 Concentrations With Incident, Sporadic Colorectal Adenoma Risk According to Common Vitamin D-Binding Protein Isoforms.

Concentration of 25-hydroxyvitamin D3 (25(OH)D3), the main circulating form of vitamin D, is inversely associated with incident, sporadic colorectal adenoma risk. We investigated whether this association differs by 2 functional variants in the vitamin D-binding protein (DBP) gene, group-specific component (GC), that encode for common protein isoforms Gc1s, Gc1f, and Gc2 linked to differences in vitamin D metabolism. We pooled data (418 patients with adenoma and 524 polyp-free control subjects) from 3 colonoscopy-based case-control studies (Minnesota, 1991-1994; North Carolina, 1994-1997; South Carolina, 2002). We estimated 25(OH)D3-adenoma associations, stratified by DBP isoforms, using multivariable logistic regression. Higher 25(OH)D3 concentrations were inversely associated with colorectal adenoma risk among those with the Gc2 isoform (per 10-ng/mL increase in 25(OH)D3, odds ratio = 0.71, 95% confidence interval: 0.56, 0.90), but not among those with only Gc1 isoforms (odds ratio = 1.07, 95% confidence interval: 0.87, 1.32; P for interaction = 0.03). Thus, the vitamin D-incident, sporadic colorectal adenoma association may differ by common DBP isoforms, and patients with the Gc2 isoform may particularly benefit from maintaining higher circulating 25(OH)D3 concentrations for adenoma prevention.

Associations of mitochondrial polymorphisms with sporadic colorectal adenoma.

Somatic mutations in mitochondrial DNA have been reported in colorectal adenomatous polyps (adenomas), the precursors to most colorectal cancers. However, there are no reports of associations of germline variation in mitochondrial DNA with adenoma risk. We investigated associations of germline polymorphisms in the displacement loop (D-loop) and non-D-loop region of the mitochondrial genome with incident, sporadic colorectal adenoma in three pooled colonoscopy-based case-control studies (n = 327 adenoma cases, 420 controls) that used identical methods for case and risk factor ascertainment. We sequenced a 1124 bp fragment to identify all genetic variation in the mitochondrial D-loop region, and used the Sequenom platform to genotype 64 tagSNPs in the non-D-loop region. We used multivariable unconditional logistic regression to estimate associations of the polymorphisms with adenoma. The odds ratios (OR) for associations of four polymorphisms in the HV1 region (mt16294, mt16296, mt16278, mt16069) with adenoma were 2.30, 2.63, 3.34, and 0.56, respectively; all 95% confidence intervals (CI) excluded 1.0, however, after correction for multiple comparisons, none of the findings remained statistically significant. Similar results were found for six polymorphisms in the non-D-loop region. In the HV1 region poly C tract, relative to those with 5 repeats, the ORs for those with fewer or more repeats were, respectively, 2.29 (95%CI 1.07-4.89) and 0.63 (95%CI 0.36-1.08), but repeat numbers in the HV2 region were not associated with adenoma. These findings suggest that mitochondrial D-loop HV1 region polymorphisms may be associated with colorectal adenoma risk and support further investigation.

Genome-wide association study of homocysteine in African Americans from the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Coronary Artery Risk in Young Adults study.

Homocysteine (Hcy) is a heritable biomarker for CVD, peripheral artery disease, stroke, and dementia. Little is known about genetic associations with Hcy in individuals of African ancestry. We performed a genome-wide association study for Hcy in 4927 AAs from the Jackson Heart Study (JHS), the Multi-Ethnic Study of Atherosclerosis (MESA), and the Coronary Artery Risk in Young Adults (CARDIA) study. Analyses were stratified by sex and results were meta-analyzed within and across sex. In the sex-combined meta-analysis, we observed genome-wide significant evidence (p < 5.0 × 10-8) for the NOX4 locus (lead variant rs2289125, ß = -0.15, p = 5.3 × 1011). While the NOX4 locus was previously reported as associated with Hcy in European-American populations, rs2289125 remained genome-wide significant when conditioned on the previously reported lead variants. Previously reported genome-wide significant associations at NOX4, MTR, CBS, and MMACHC were also nominally (p < 0.050) replicated in AAs. Associations at the CPS1 locus, previously reported in females only, also was replicated specifically in females in this analysis, supporting sex-specific effects for this locus. These results suggest that there may be a combination of cross-population and population-specific genetic effects, as well as differences in genetic effects between males and females, in the regulation of Hcy levels.

Circulating γ-Tocopherol Concentrations Are Inversely Associated with Antioxidant Exposures and Directly Associated with Systemic Oxidative Stress and Inflammation in Adults.

Background: Although α- and γ-tocopherol are co-consumed antioxidants, circulating γ-tocopherol concentrations were paradoxically found to be inversely associated with total vitamin E intake and circulating α-tocopherol concentrations. There are limited data on this apparent paradox or on determinants of circulating γ-tocopherol concentrations. Objective: To help clarify possible determinants of circulating γ-tocopherol concentrations, we investigated associations of circulating γ-tocopherol concentrations with various dietary and lifestyle factors and biomarkers of oxidative stress and inflammation. Methods: We pooled cross-sectional data from 2 outpatient, adult, elective colonoscopy populations (pooled n = 419) on whom extensive dietary, lifestyle, and medical information was collected, and the following plasma concentrations were measured: α- and γ-tocopherol (via HPLC), F2-isoprostanes (FiPs; via gas chromatography-mass spectrometry), and high-sensitivity C-reactive protein (hsCRP; via latex-enhanced immunonephelometry). Multivariable general linear models were used to assess mean γ-tocopherol differences across quantiles of plasma antioxidant micronutrients, FiPs, and hsCRP; an oxidative balance score [OBS; a composite of anti- and pro-oxidant dietary and lifestyle exposures (a higher score indicates higher antioxidant relative to pro-oxidant exposures)]; and multiple dietary and lifestyle factors. Results: Adjusted for serum total cholesterol, mean γ-tocopherol concentrations among those in the highest relative to the lowest tertiles of circulating α-tocopherol and ß-carotene, the OBS, and total calcium and dietary fiber intakes were 31.0% (P < 0.0001), 29.0% (P < 0.0001), 27.6% (P = 0.0001), 29.7% (P < 0.0001), and 18.6% (P = 0.008) lower, respectively. For those in the highest relative to the lowest tertiles of circulating FiPs and hsCRP, mean γ-tocopherol concentrations were 50% (P < 0.0001) and 39.0% (P < 0.0001) higher, respectively. Conclusions: These findings support the conclusion that circulating γ-tocopherol concentrations are inversely associated with antioxidant exposures and directly associated with systemic oxidative stress and inflammation in adults. Additional research on possible mechanisms underlying these findings and on whether circulating γ-tocopherol may serve as a biomarker of oxidative stress, inflammation, or both is needed.

Transethnic insight into the genetics of glycaemic traits: fine-mapping results from the Population Architecture using Genomics and Epidemiology (PAGE) consortium.

AIMS/HYPOTHESIS: Elevated levels of fasting glucose and fasting insulin in non-diabetic individuals are markers of dysregulation of glucose metabolism and are strong risk factors for type 2 diabetes. Genome-wide association studies have discovered over 50 SNPs associated with these traits. Most of these loci were discovered in European populations and have not been tested in a well-powered multi-ethnic study. We hypothesised that a large, ancestrally diverse, fine-mapping genetic study of glycaemic traits would identify novel and population-specific associations that were previously undetectable by European-centric studies. METHODS: A multiethnic study of up to 26,760 unrelated individuals without diabetes, of predominantly Hispanic/Latino and African ancestries, were genotyped using the Metabochip. Transethnic meta-analysis of racial/ethnic-specific linear regression analyses were performed for fasting glucose and fasting insulin. We attempted to replicate 39 fasting glucose and 17 fasting insulin loci. Genetic fine-mapping was performed through sequential conditional analyses in 15 regions that included both the initially reported SNP association(s) and denser coverage of SNP markers. In addition, Metabochip-wide analyses were performed to discover novel fasting glucose and fasting insulin loci. The most significant SNP associations were further examined using bioinformatic functional annotation. RESULTS: Previously reported SNP associations were significantly replicated (p ≤ 0.05) in 31/39 fasting glucose loci and 14/17 fasting insulin loci. Eleven glycaemic trait loci were refined to a smaller list of potentially causal variants through transethnic meta-analysis. Stepwise conditional analysis identified two loci with independent secondary signals (G6PC2-rs477224 and GCK-rs2908290), which had not previously been reported. Population-specific conditional analyses identified an independent signal in G6PC2 tagged by the rare variant rs77719485 in African ancestry. Further Metabochip-wide analysis uncovered one novel fasting insulin locus at SLC17A2-rs75862513. CONCLUSIONS/INTERPRETATION: These findings suggest that while glycaemic trait loci often have generalisable effects across the studied populations, transethnic genetic studies help to prioritise likely functional SNPs, identify novel associations that may be population-specific and in turn have the potential to influence screening efforts or therapeutic discoveries. DATA AVAILABILITY: The summary statistics from each of the ancestry-specific and transethnic (combined ancestry) results can be found under the PAGE study on dbGaP here: https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000356.v1.p1.

Correction to: Transethnic insight into the genetics of glycaemic traits: fine-mapping results from the Population Architecture using Genomics and Epidemiology (PAGE) consortium.

The authors regret that Yinchang Lu's name incorrectly included a middle initial in the author list. The details given in this erratum are correct.

Association of exome sequences with plasma C-reactive protein levels in >9000 participants.

C-reactive protein (CRP) concentration is a heritable systemic marker of inflammation that is associated with cardiovascular disease risk. Genome-wide association studies have identified CRP-associated common variants associated in ∼25 genes. Our aims were to apply exome sequencing to (1) assess whether the candidate loci contain rare coding variants associated with CRP levels and (2) perform an exome-wide search for rare variants in novel genes associated with CRP levels. We exome-sequenced 6050 European-Americans (EAs) and 3109 African-Americans (AAs) from the NHLBI-ESP and the CHARGE consortia, and performed association tests of sequence data with measured CRP levels. In single-variant tests across candidate loci, a novel rare (minor allele frequency = 0.16%) CRP-coding variant (rs77832441-A; p.Thr59Met) was associated with 53% lower mean CRP levels (P = 2.9 × 10(-6)). We replicated the association of rs77832441 in an exome array analysis of 11 414 EAs (P = 3.0 × 10(-15)). Despite a strong effect on CRP levels, rs77832441 was not associated with inflammation-related phenotypes including coronary heart disease. We also found evidence for an AA-specific association of APOE-ε2 rs7214 with higher CRP levels. At the exome-wide significance level (P < 5.0 × 10(-8)), we confirmed associations for reported common variants of HNF1A, CRP, IL6R and TOMM40-APOE. In gene-based tests, a burden of rare/lower frequency variation in CRP in EAs (P ≤ 6.8 × 10(-4)) and in retinoic acid receptor-related orphan receptor α (RORA) in AAs (P = 1.7 × 10(-3)) were associated with CRP levels at the candidate gene level (P < 2.0 × 10(-3)). This inquiry did not elucidate novel genes, but instead demonstrated that variants distributed across the allele frequency spectrum within candidate genes contribute to CRP levels.

Trans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci.

Most body mass index (BMI) genetic loci have been identified in studies of primarily European ancestries. The effect of these loci in other racial/ethnic groups is less clear. Thus, we aimed to characterize the generalizability of 170 established BMI variants, or their proxies, to diverse US populations and trans-ethnically fine-map 36 BMI loci using a sample of >102,000 adults of African, Hispanic/Latino, Asian, European and American Indian/Alaskan Native descent from the Population Architecture using Genomics and Epidemiology Study. We performed linear regression of the natural log of BMI (18.5-70 kg/m2) on the additive single nucleotide polymorphisms (SNPs) at BMI loci on the MetaboChip (Illumina, Inc.), adjusting for age, sex, population stratification, study site, or relatedness. We then performed fixed-effect meta-analyses and a Bayesian trans-ethnic meta-analysis to empirically cluster by allele frequency differences. Finally, we approximated conditional and joint associations to test for the presence of secondary signals. We noted directional consistency with the previously reported risk alleles beyond what would have been expected by chance (binomial p < 0.05). Nearly, a quarter of the previously described BMI index SNPs and 29 of 36 densely-genotyped BMI loci on the MetaboChip replicated/generalized in trans-ethnic analyses. We observed multiple signals at nine loci, including the description of seven loci with novel multiple signals. This study supports the generalization of most common genetic loci to diverse ancestral populations and emphasizes the importance of dense multiethnic genomic data in refining the functional variation at genetic loci of interest and describing several loci with multiple underlying genetic variants.

DNA base excision repair genetic risk scores, oxidative balance, and incident, sporadic colorectal adenoma.

Associations of individual base excision repair (BER) genotypes with colorectal adenoma risk are unclear, but likely modest. However, genetic risk scores (GRS) that aggregate information from multiple genetic variants might be useful for assessing genetic predisposition to colorectal adenoma. We analyzed data pooled from three colonoscopy-based case-control studies of incident, sporadic colorectal adenoma (n = 488 cases, 604 controls) that collected blood for genotyping and extensive dietary and other data. We randomly split our population sample into training samples (half of the participants) and validation samples (the remaining participants) 10 times. Associations of 65 individual single nucleotide polymorphisms (SNPs) in 15 BER genes were assessed in the training samples and used to combine information from multiple risk variants into a BER GRS among the validation samples using unweighted and weighted methods. We also combined 15 extrinsic exposures with known pro- or antioxidant properties into an oxidative balance score (OBS). Associations of the BER GRS with colorectal adenoma, overall and jointly with the OBS, were assessed using multivariable logistic regression. The odds ratio for those in the highest relative to the lowest tertile of the weighted BER GRS was 2.07 (95% confidence interval, 1.26-3.40; ptrend = 0.01). Relative to those with both a low GRS and a high (more antioxidant) OBS, the estimated direct association for those with both a high BER GRS and a low OBS was stronger than for those in other GRS/OBS categories. Our findings suggest that BER genotypes collectively may be associated with incident sporadic colorectal adenomas.

Soluble MICA is elevated in pancreatic cancer: Results from a population based case-control study.

Pancreatic cancer is diagnosed at a late stage and has one of the highest cancer mortality rates in the United States, creating an urgent need for novel early detection tools. A candidate biomarker for use in early detection is the soluble MHC class I-related chain A (s-MICA) ligand, which pancreatic tumors shed to escape immune detection. The objective of this study was to define the association between s-MICA levels and pancreatic cancer, in a population-based case-control study. S-MICA was measured in 143 pancreatic cancer cases and 459 controls. Unconditional logistic regression was used to calculate odds ratio (OR) for pancreatic cancer and 95% confidence intervals (CI). There was a positive association between increasing s-MICA levels and pancreatic cancer: compared to the lowest tertile, the ORs for pancreatic cancer were 1.25 (95%CI: 0.75-2.07) and 2.10 (95%CI: 1.29-3.42) in the second and highest tertiles, respectively (P-trend = 0.02). Our study supports previous work demonstrating a positive association between plasma s-MICA levels and pancreatic cancer.

Collagen Turnover Markers in Relation to Future Cardiovascular and Noncardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Sustained remodeling of extracellular matrix can compromise organs and tissues. Procollagen type III N-terminal propeptide (PIIINP) and collagen type I carboxy-terminal telopeptide (ICTP) reflect collagen synthesis and degradation. We studied their predictive value for future death and disease. METHODS: A total of 3068 men and women in the Multi-Ethnic Study of Atherosclerosis who were free of cardiovascular disease (CVD) and in generally good health had a baseline blood sample taken for ICTP and PIIINP. Median follow-up was 13.0 years. Among 4 primary outcomes, CVD events (n = 697) were adjudicated, death (n = 571) was by death certificate, and chronic inflammatory-related severe hospitalization and death (ChrIRD, n = 726) and total cancer (n = 327) were classified using International Classification of Diseases codes. We used Poisson regression to study baseline ICTP and PIIINP relative to these outcomes. RESULTS: Mean (SD) PIIINP was 5.47 (1.95) µg/L and ICTP was 3.37 (1.70) µg/L. PIIINP and ICTP were highly correlated with each other and with estimated glomerular filtration rate (eGFR). Adjustment for age and eGFR attenuated relative risks, remaining 20%-30% per SD of both PIIINP and ICTP in prediction for total death and ChrIRD, and of PIIINP for cancer, with little additional attenuation by adjusting for risk factors and inflammatory biomarkers. CVD outcome was generally unrelated to PIIINP but became marginally inversely related to ICTP in the most adjusted model. CONCLUSIONS: The collagen biomarkers PIIINP and ICTP, in part through pathophysiologically parallel associations with renal function, predicted ChrIRD and total death. Moreover, PIIINP predicted future cancer. These collagen markers may help differentiate healthy from unhealthy aging.

Plasma F2-isoprostanes Are Positively Associated with Glycemic Load, but Inversely Associated with Dietary Polyunsaturated Fatty Acids and Insoluble Fiber in Postmenopausal Women.

Background: Dietary factors, such as antioxidant nutrients, contribute significantly to the maintenance of an appropriate balance between antioxidant defense and free radical production in the body.Objective: The objective of this study was to examine the relation between oxidative stress as assessed by plasma F2-isoprostane (IsoP) concentration, glycemic load (GL), glycemic index (GI), intake of antioxidant nutrients, dietary fiber, and polyunsaturated fatty acids (PUFAs).Methods: This study was a cross-sectional secondary analysis of baseline data collected from a random sample of 269 postmenopausal women participating in the Minnesota Green Tea Trial. GL, GI, and dietary variables were calculated from the diet history questionnaire. Subjects filled out surveys about the use of anti-inflammatory drugs and physical activity. Plasma IsoP concentration was assessed by GC-mass spectrometry. IsoP concentrations were compared across quartiles of GL, GI, insoluble fiber, PUFAs, and antioxidant nutrients with the use of linear regression.Results: Antioxidant supplement intake, including zinc, copper, vitamin C and vitamin E, was reported by >60% of the participants. Mean intake of PUFAs was 12.5 g. Mean plasma IsoP concentrations increased from 34 to 36.7 pg/mL in the lowest quartiles of GL and GI, respectively, to 45.2 and 41.6 pg/mL, respectively, in the highest quartiles (P-trend = 0.0014 for GL and P-trend = 0.0379 for GI), whereas mean IsoP concentrations decreased from 41.8 pg/mL in the lowest quartile of PUFAs to 34.9 pg/mL in the highest quartile (P-trend = 0.0416). Similarly, mean IsoP concentrations decreased from 44.4 pg/mL in the lowest quartile of insoluble fiber to 36 pg/mL in the highest quartile (P-trend = 0.0243) after adjustment for potential confounders.Conclusions: We concluded that dietary PUFAs and insoluble fiber are inversely associated with oxidative stress whereas GL and GI are positively associated with oxidative stress in postmenopausal women. This trial was registered at clinicaltrials.gov as NCT00917735.